Extracellular Matrix

Question 1

Functions of ECM

Answer 1

• cellular division
• motility
• differentiation
• adhesion
• structure

Question 2

Components of ECM

Answer 2

• Structural Proteins = collagens and elastins (strength and flexibility)
• Proteoglycans =protein-polysaccharides complexes (matrix for collagen and elastins to be embedded in)
• Adhesive Glycoproteins = Fibronectins and Laminins (attach cells to matrix)

Question 3

Collagens

Answer 3

• Structural Proteins
• Most Abundant Protein in vertebrates (25% - 30% of total body protein)
• Abundant in tendons and ligaments
• Secreted by several connective tissue cells (ex-fibroblasts)
• Rigid Triple Helix structure with polypeptide chains high in glysine, hydroxylysine, and hydroxyproline
• Have incredible strength

Question 4

Collagen Cross Linking

Answer 4

When Produced: Collagen bundles cross-linked which strengthens collagen bundle and helps withstand high stress

With Aging:
Abnormal Crosslinking which leads to loss of joint function

Question 5

hypermobility

Answer 5

deficiency in collagen synthesis or assembly (collagenase)

Question 6

Elastin provides….

Answer 6

• flexibility

- elasticity

Question 7

What is elastin?

Answer 7

• proteins rich in glycine and proline

- molecules of elastin are crosslinked BETWEEN lysines

Question 8

Why is elastin flexible?

Answer 8

• can form variety of confirmations
• the tension in it allows for stretching
• no tension when relaxed so no stretching

Question 9

Why does skin become wrinkled and joints become inflexible as we age?

Answer 9

Elastins are lost as we age

Question 10

What is supravalvular aortic stenosis (SVAS)?

Answer 10

• inherited obstructive vascular diesease that affects the aorta, carotid, coronary and pulmonary arteries
• Mutation in elastin gene disrupts elastin protein synthesis and result in narrowing of aorta or pulmonary vessels
• This can lead to a heart murmur and ventricular hypertrophy
• Not frequently seen
• defect is located just above the aortic valve
• Affects some large dog breeds = Newfoundland, Golden Retriever, Boxer, and Rottweiler

Question 11

Proteoglycans

Answer 11

• Make up Gel-like network that surrounds collagen and elastin
• Proteoglycans are glycoproteins

Question 12

What are glycoproteins?

Answer 12

• Protein with glycoaminogylcans

- Up to 95% carbohydrate

Question 13

Functions of Proteoglycans

Answer 13

• Receptors
• Filtration
• Shock Absorption
• Trap water = >50% Times Their Weight

Question 14

Hyaluronate

Answer 14

• Proteoglycan that acts as the backbone in cartilage
• also acts a free molecule

Function

• lubricates any place with friction = joints
• found on suface of migrating cells
  - disappears upon cell-to-cell contact
  
  • facilitate cell migration by making matrix more water-soluble

Question 15

T/F: Hyaluronan is quite large in comparison to other ECM components

Answer 15

True.

Hyaluronan is much larger than other ECM components.

Question 16

Glycosaminoglycan Side Chains can be used for classification. What are the 3 types and their uses?

Answer 16

• Chondroitin Sulfate = cartilage/ osteoarthritis
• Keratan Sulfate = cornea, cartilage, bone, cushion
• Heparin/ Heparin Sulfate = Anticoagulant, bind growth factors, important role in inflammation, entry of virus into cells (herpes, rabies)

Question 17

Heparin/ Heparan Sulfate

Answer 17

• Heparan Sulfate is found in every cell of body and has side chains made of D-glucosamine/ L-iduronic acid
• Heparin is one member of the Heparan Sulfate Family and serves as an anticoagulant
• Other Family Members bind growth factors, play an important role in inflammation, and entry of viruses into cell like herpes and rabies

Question 18

Fibronectin

Answer 18

• widely distributed
• most common adhesive glycoprotein
• can be soluble, insoluble, or partialy soluble (can be from same gene due to alternative splicing)

Question 19

Roles of Fibronectin

Answer 19

• maintains cell shape
• possible role in cancer
• blood clotting
• wound healing
• cell movement

Question 20

Fibronectins Role in Cancer

Answer 20

• Many carcinomas are unable to synthesize fibronectins, lose normal shape, and cells detach from ECM
• Give fibronectin and cells revert to normal shape, bind to ECM, and are no longer malignant

Question 21

How does fibronectin connect into blood clotting?

Answer 21

-recognizes fibrin (blood clotting protein) that is attached to blood platelets

Question 22

What does fibronectin do in wound healing?

Answer 22

guides immune cells to wound

Question 23

Where are laminins mainly located?

Answer 23

Basal Laminae

Question 24

Basal Laminae

Answer 24

• Thin sheet of EC material (approx. 50nm thick)
• underlies epithelial cells
• separates ECM from epi cells
• Surrounds muscle cells, fat cells, and Schwann cells

Question 25

Properties of Basal Lamina

Answer 25

- Structural Support - Permeability Barrier = kidney -> can let in small proteins, but not blood into urine - Cell Migration

Question 26

T/F: When ECM has been damaged and is remodeled, it is laid down in the same pattern as it was originally.

Answer 26

False. ECM is initially very well organized and structured. After damage and remodeling, it is not well organized and structured.

Question 27

Why is ECM constantly being remodeled?

Answer 27

- growth - changes in mechanical forces - heal

Question 28

Synthesis Of ECM

Answer 28

- Under Transcriptional (genesis) Control by parent cell types * osteoblasts * chondrocytes * fibrocytes - Cells respond to: * paracrine signaling by growth factors * physical (lack of) contact with other cells and ECM

Question 29

Degrading ECM

Answer 29

-Accomplished by enzymes = metalloproteinases and serine proteases

Question 30

What does metalloproteinases need for ECM?

Answer 30

- require Zinc or Calcium | - usually specific for 1 ECM Component

Question 31

How do serine proteases play into degrading ECM?

Answer 31

- cleave protein sequences at serine residues | - work with metalloproteinases

Question 32

How can ECM degradation be stopped?

Answer 32

- Tissue Inhibitors of Metalloproteinases (TIMP1, 2 ,3, and 4) that form high affinity complexes with metalloproteinases that are irreversible - Serine Protease Inhibitors that inactivate serine proteases

Question 33

Alpha 1-antitrypsin deficiency

Answer 33

- Alpha 1-antitrypsin is produced in liver and macrophages = protects lungs from neutrophil elastase enzyme, which can disrupt connective tissue - Deficiency caused by defective production of alpha 1-antitrypsin - Emphysema/COPD and liver disease (cirrhosis) can result - Treatment is IV infusions of alpha 1-antitrypsin

Question 34

Panniculitis

Answer 34

- alpha 1-antitrypsin deficiency in dogs leading to rare skin condition - characterized by hardened skin with painful lumps or patches - can vary in severity - can occur at any age